Lercanidipine boosts the efficacy of mesenchymal stem cell therapy in 3-NP-induced Huntington's disease model rats via modulation of the calcium/calcineurin/NFATc4 and Wnt/β-catenin signalling pathways

Neurochem Int. 2019 Dec:131:104548. doi: 10.1016/j.neuint.2019.104548. Epub 2019 Sep 17.

Abstract

3-Nitropropionic acid (3-NP) induces a spectrum of Huntington's disease (HD)-like neuropathologies in the rat striatum. The present study aimed to demonstrate the neuroprotective effect of lercanidipine (LER) in rats with 3-NP-induced neurotoxicity, address the possible additional protective effect of combined treatment with bone marrow-derived mesenchymal stem cells (BM-MSCs) and LER, and investigate the possible involvement of the Ca2+/calcineurin (CaN)/nuclear factor of activated T cells c4 (NFATc4) and Wnt/β-catenin signalling pathways. Rats were injected with 3-NP (10 mg/kg/day, i.p.) for two weeks and were divided into four subgroups; the first served as the control HD group, the second received a daily dose of LER (0.5 mg/kg, i.p.), the third received a single injection of BM-MSCs (1 x 106/rat, i.v.) and the last received a combination of both BM-MSCs and LER. The combined therapy improved motor and behaviour performance. Meanwhile, this treatment led to a marked reduction in striatal cytosolic Ca2+, CaN, tumour necrosis factor-alpha, and NFATc4 expression and the Bax/Bcl2 ratio. Combined therapy also increased striatal brain-derived neurotrophic factor, FOXP3, Wnt, and β-catenin protein expression. Furthermore, haematoxylin-eosin and Nissl staining revealed an amelioration of striatum tissue injury with the combined treatment. In conclusion, the current study provides evidence for a neuroprotective effect of LER and/or BM-MSCs in 3-NP-induced neurotoxicity in rats. Interestingly, combined LER/BM-MSC therapy was superior to cell therapy alone in inhibiting 3-NP-induced neurological insults via modulation of the Ca2+/CaN/NFATc4 and Wnt/β-catenin signalling pathways. LER/BM-MSC combined therapy may represent a feasible approach for improving the beneficial effects of stem cell therapy in HD.

Keywords: 3-Nitropropionic acid; BM-MSCs; Ca(2+)/CaN/NFATc4; Huntington's disease; Lercanidipine; Wnt/β-catenin.

MeSH terms

  • Animals
  • Behavior, Animal / drug effects
  • Calcineurin / drug effects
  • Calcium Channel Blockers / therapeutic use*
  • Calcium Signaling / drug effects
  • Cytosol / drug effects
  • Cytosol / metabolism
  • Dihydropyridines / therapeutic use*
  • Huntington Disease / chemically induced
  • Huntington Disease / drug therapy
  • Huntington Disease / therapy*
  • Male
  • Mesenchymal Stem Cell Transplantation / methods*
  • NFATC Transcription Factors / drug effects
  • Nerve Tissue Proteins / drug effects
  • Nitro Compounds
  • Propionates
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Rats
  • Rats, Wistar
  • Signal Transduction / drug effects*
  • Tumor Necrosis Factor-alpha / metabolism
  • Wnt Signaling Pathway / drug effects
  • bcl-2-Associated X Protein / metabolism
  • beta Catenin / drug effects

Substances

  • Bax protein, rat
  • Bcl2 protein, rat
  • Calcium Channel Blockers
  • Dihydropyridines
  • NFATC Transcription Factors
  • Nerve Tissue Proteins
  • Nfatc4 protein, rat
  • Nitro Compounds
  • Propionates
  • Proto-Oncogene Proteins c-bcl-2
  • Tumor Necrosis Factor-alpha
  • bcl-2-Associated X Protein
  • beta Catenin
  • Calcineurin
  • 3-nitropropionic acid
  • lercanidipine